The human immunodeficiency virus HIV is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease characterized by the destruction of the immune system, particularly of the CD4+ T-cell, with attendant susceptibility to opportunistic infections. HIV infection is also associated with a precursor AIDS-related complex (ARC), a syndrome characterized by symptoms such as persistent generalized lymphadenopathy, fever and weight loss.
Currently available chemotherapy targets two crucial viral enzymes: HIV protease and HIV reverse transcriptase. (J. S. G. Montaner et al., Biomed. & Pharmacother. 1999 53:63-72; R. W. Shafer and D. A. Vuitton, Biomed. & Pharmacother. 1999 53:73-86; E. De Clercq, Curr. Med. Chem. 2001 8:1543-1572). Two general classes of RTI inhibitors have been identified: nucleoside reverse transcriptase inhibitors (NRTI) and non-nucleoside reverse transcriptase inhibitors. Currently the CCR5 co-receptor has emerged as a potential target for anti-HIV chemotherapy (D. Chantry, Expert Opin. Emerg. Drugs 2004 9(1):1-7; C. G. Barber, Curr. Opin. Invest. Drugs 2004 5(8):851-861; D. Schols, Curr. Topics Med. Chem. 2004 4(9):883-893; N. A. Meanwell and J. F. Kadow, Curr. Opin. Drug Discov. Dev. 2003 6(4):451-461). Drugs targeted at new enzymatic targets have entered the market including integrase inhibitors typified by Raltegravir (Merck) has been approved by the FDA and Elvitegravir (Gilead Sciences and Japan Tobacco) is in phase II trials. The CCR5 antagonist maraviroc (SELZENTRY™, Pfizer) has also been approved by the FDA for anti-HIV-1 therapy.
NNRTIs were first discovered in 1989. NNRTI are allosteric inhibitors which bind reversibly at a nonsubstrate-binding site on the HIV reverse transcriptase thereby altering the shape of the active site or blocking polymerase activity (R. W. Buckheit, Jr., Expert Opin. Investig. Drugs 2001 10(8)1423-1442; E. De Clercq, Antiviral Res. 1998 38:153-179; E. De Clercq, Current medicinal Chem. 2001 8(13):1543-1572; G. Moyle, Drugs 2001 61 (1):19-26). Initially viewed as a promising class of compounds, in vitro and in vivo studies quickly revealed the NNRTIs presented a low barrier to the emergence of drug resistant HIV strains and class-specific toxicity. Although over thirty structural classes of NNRTIs have been identified in the laboratory, only three compounds have been approved for HIV therapy: efavirenz, nevirapine and delavirdine. There remains a need for safer drugs with activity against wild type and commonly occurring resistant strains of HIV.
5-Aralkyl-2,4-dihydro-[1,2,4]triazol-3-ones are non-nucleoside reverse transcriptase inhibitors have been disclosed by J. P. Dunn et al. in U.S. Pat. No. 7,208,509 granted Apr. 24, 2007 and by J. P. Dunn et al. in U.S. Publication No. 20060025462 filed Jun. 27, 2005. Pyridazinone non-nucleoside reverse transcriptase inhibitors have been disclosed by J. P. Dunn et al. in U.S. Pat. No. 7,208,509 granted Mar. 13, 2007 and U.S. Publication No. 20050215554 published Sep. 28, 2005. A process for the preparation of pyridazinone non-nucleoside reverse transcriptase inhibitors was disclosed by D. J. Kertesz in U.S. Patent Publication 20050234236 published Oct. 20, 2005.
